For normal cells, each cycle of division is a step toward death. The process gradually erodes the enzyme caps, or telomeres, that protect the ends of the cell's all-important chromosomes. Cancer cells, however, have figured out a way to cheat death by rebuilding their telomeres. About 90 percent do this by reactivating the gene for an enzyme called telomerase. But the remaining 10 percent achieve immortality without turning on the telomerase gene. Research published today in the online early edition of the Proceedings of the National Academy of Sciences has pinpointed an alternative protein that these cells appear to use. The discovery could lead to new ways to combat cancer.
David Sinclair of Harvard Medical School and his colleagues focused on a gene known as WRN. Its absence in humans causes Werner's syndrome, a rare disease characterized by greatly accelerated aging. They found that the absence of a version of WRN in yeast resulted in cells that did not survive beyond the normal number of cell divisions. In contrast, those yeast cells endowed with the WRN equivalent attained the ability to divide endlessly.
The WRN protein is basically a longevity molecule, Sinclair explains. "Cancer cells may utilize the WRN protein for their own purposes to become immortal and get around the barrier to tumorigenesis and cancer formation." If so, blocking the WRN protein in the 10 percent of cancers that maintain their telomeres without activating the telomerase gene could prove to be an effective way to fight tumors. What's more, that strategy could, in theory, also be applied to the other 90 percent of tumor cells, which when deprived of telomerase sometimes switch to the other telomere maintenance strategy.
Because WRN plays a critical role in cell life, blocking the protein in all cells as a means of treating cancer might not be a prudent approach. On the other hand, Sinclair notes, considering that Werner's patients don't develop the early aging symptoms until their mid- to late teens, systemic delivery for short periods might be feasible. "What I foresee is either just have a short-term dose of this drug or target it to cells that are cancerous," he remarks. "Of course, getting this drug to cancer cells is the challenge."